Coxiella burnetii is an obligate intracellular gram-negative bacterium that causes acute Q fever and chronic infections in humans. It is an understudied category B select agent and can be transmitted via aerosol, thus creation of a safe and effective vaccine to prevent Q fever remains an important public health and national biosecurity goal. The long-term goal of this program is to develop new approaches to discover safe, effective vaccines against aerosol-transmitted intracellular bacterial pathogens. The objective of this application, which is an essential step towards this goal, is to identify the epitopes on C. burnetii phase I lipopolysaccharide (PI-LPS) that can confer protection against pulmonary infection with aerosolized C. burnetii. To achieve this objective, we will test the central hypothesis that O antigen of C. burnetii PI-LPS is the key antigen to confer protective immunity against Q fever. The purpose of this proposal is to prove the concept that peptide mimics of protective epitopes on O antigen of PI-LPS can confer protective immunity against C. burnetii infection. The proposal has two specific aims: Aim 1: to determine if O antigen of PI-LPS is the key protective antigen. We will determine if Ab against O antigen of C. burnetii PI-LPS is protective and identify the monoclonal antibodies (mAbs) that can provide protection against C. burnetii infection. We will also determine if purified O antigen from PI-LPS can confer protection against C. burnetii infection. Aim 2: to identify the peptide mimics that can confer protective immunity against C. burnetii infection. We will identify the peptide mimics that can confer protective immunity against C. burnetii infection and determine if peptide mimics of protective epitopes of O antigen can elicit protective immunity against C. burnetii infection. We will also determine if chemically synthesized peptide mimics, in the context of an adjuvant and a suitable delivery system, can provide protection against C. burnetii infection. As an outcome of this research, we expect to prove the concept that peptide mimics of protective epitopes of O antigen can elicit protective immunity against C. burnetii infection. This would have significant positive effects on human health, because it would provide information for vaccine design against Q fever, and in turn lead to development of new strategies to interfere with aerosol transmission of other dangerous intracellular bacterial pathogens.